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Page 2 of 18 Caron de Fromentel et al. Hepatoma Res 2020;6:80 I http://dx.doi.org/10.20517/2394-5079.2020.77

INTRODUCTION
Hepatocellular carcinoma (HCC) is a major public health problem, being the fourth most lethal cancer
[1]
with an increasing incidence around the world . About 90% of HCC cases can be associated with four
well-characterized underlying risk factors including chronic infection with hepatitis B and C viruses
[2]
(HBV, HCV), ethanol consumption, and non-alcoholic fatty liver disease (NAFLD) . Although the risk of
developing HCC can be reduced in patients by treatment of the underlying cause - e.g., HCV eradication
by direct-acting antivirals (DAAs) and HBV suppression by nucleos(t)ide analogs (NUCs) - strategies to
[3,4]
prevent cancer development in patients with advanced fibrosis and established cirrhosis are still lacking .
Despite the recent improvements, treatment options for HCC remain largely unsatisfactory. Currently,
curative treatment options for patients with HCC include surgical resection and loco-regional ablation,
frequently associated with tumor recurrence, and orthotopic liver transplantation, a resource-intensive
[3,4]
solution . However, due to its silent clinical character and the low sensitivity and specificity of currently
available diagnostic biomarkers, HCC is commonly diagnosed at an advanced stage, when curative
[3,4]
treatments are not feasible, leaving systemic drugs as the only option . Patients with untreated advanced
HCC carry a very poor prognosis with an expected survival of 4-6 months. Treatment modalities available
for patients with advanced HCC not eligible for curative treatment include the multikinase inhibitors
(MTKi) sorafenib and lenvatinib as first line treatment, with an increase in survival of approximately
3 months, and MTKi regorafenib or cabozantinib as second or third line treatment that enables extension
[3,4]
of survival by an additional 3 months . Immune checkpoint inhibitors (ICIs) in monotherapy achieve
[3,4]
striking tumor responses in a few patients who have hugely improved outcomes , but the low rate of
responding patients does not allow significant improvements in the median overall survival. More recently,
the combination of drugs targeting the liver microenvironment with PD1/PD-L1 inhibitors, such as the
association of bevacizumab and atezolizumab, or the combination of ICIs have shown promising results .
[3-5]

In HCC, as in numerous other tumor types, the chemoresistance is thought to be due to the existence
of a sub-population of poorly differentiated cancer cells, widely known as liver cancer stem cells (CSCs)
[6,7]
or tumor initiating cells (TICs) . The escape mechanisms are diverse, like enzymatic inactivation
[6,7]
or increased drug efflux . The microenvironment also plays an important role. By secreting growth
factors and cytokines, it favors the emergence, maintenance and survival of CSCs and their resistance
[8]
to chemotherapeutic drugs, resulting in the recurrence of more aggressive tumors . Chronic HBV and
HCV infections and alcohol abuse induce liver inflammation, fibrosis, and cirrhosis. This pathological
microenvironment exhibits alterations in cytokine secretion, extra-cellular matrix components and
stiffness, angiogenesis, and liver resident immune cells. Moreover, the abnormal activation of signaling
pathways, several of them strongly involved in stemness, are observed in liver fibrosis and cirrhosis [9,10] . All
these alterations could contribute to the emergence of cellular clones with characteristics of liver CSCs, as
[8]
shown in other tumor types and subsequently to HCC initiation and development.

Understanding the mechanisms responsible for liver CSC maintenance and survival is therefore an
important step in the search of efficient therapies for HCC. CSCs exploit signaling pathways essential for
self-renewal, proliferation and differentiation that are usually used by stem cells in physiological situations.
Wnt/β-catenin, Hedgehog, Notch, and TGFβ are the main pathways found activated in hepatic CSCs [11-14] .
For some of them, this activation has been associated with the expression of cell surface markers, such as
EpCAM for the Wnt/β-catenin pathway or CK19 for the TGFβ pathway, and with poorly differentiated
tumors, drug resistance and worse prognosis [15-17] .

In addition to these pathways, another key player of CSCs is the p53 family. In this review, we summarize
the main functions of p53 and the p53 family, as well as the mechanisms that lead to their functional
inactivation in tumors. We describe the alterations of p53 functions that favor the emergence of CSCs
with a particular focus on liver CSCs. Finally, we highlight the close connection between the p53 family